GDC-0449-A potent inhibitor of the hedgehog pathway

被引：321

作者：

Robarge, Kirk D. ^{[1
]}

Brunton, Shirley A. ^{[2
]}

Castanedo, Georgette M. ^{[1
]}

Cui, Yong ^{[1
]}

Dina, Michael S. ^{[1
]}

Goldsmith, Richard ^{[1
]}

Gould, Stephen E. ^{[3
]}

Guichert, Oivin ^{[3
]}

Gunzner, Janet L. ^{[1
]}

Halladay, Jason ^{[1
]}

Jia, Wei ^{[1
]}

Khojasteh, Cyrus ^{[1
]}

Koehler, Michael F. T. ^{[1
]}

Kotkow, Karen ^{[3
]}

La, Hank ^{[1
]}

LaLonde, Rebecca L. ^{[1
]}

Lau, Kevin ^{[1
]}

Lee, Leslie ^{[1
]}

Marshall, Derek ^{[1
]}

Marsters, James C., Jr. ^{[1
]}

Murray, Lesley J. ^{[1
]}

Qian, Changgeng ^{[3
]}

Rubin, Lee L. ^{[3
]}

Salphati, Laurent ^{[1
]}

Stanley, Mark S. ^{[1
]}

Stibbard, John H. A. ^{[2
]}

Sutherlin, Daniel P. ^{[1
]}

Ubhayaker, Savita ^{[1
]}

Wang, Shumei ^{[1
]}

Wong, Susan ^{[1
]}

Xie, Minli ^{[1
]}

机构：

[1] Genentech Inc, Small Mol Drug Discovery, San Francisco, CA 94080 USA

[2] Evotec, Abingdon OX14 4RX, Oxon, England

[3] Curis Inc, Cambridge, MA 02138 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 19期

关键词：

GDC-0449; Hedgehog pathway; Small molecule inhibitor; SIGNALING PATHWAY; HUMAN HOMOLOG; MEDULLOBLASTOMA; REQUIREMENT; MUTATIONS; GROWTH; GENE;

D O I：

10.1016/j.bmcl.2009.08.049

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5 mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：5576 / 5581

页数：6

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